Abstract
Objectives: The current study aimed to compare the
efficacy of the two different prophylactic antibiotic regimens (2-days
vs. 7-days) in preventing surgical site infection in coronary artery
bypass grafting (CABG).
Methods: Patients undergoing CABG were included in this
randomized, double-blind, placebo-controlled trial. From 2016 to 2017,
370 cases were allocated to one of two groups. The groups received
prophylactic antibiotic therapy for either 2-days or 7-days. All CABG
patients were followed for days for surgical site infections. Two of the
patients died after surgery, and 3 patients did not show up during the
three-month follow-up evaluation and thus did not meet the study
criteria.
Results: Of the remaining 365 patients who participated
in the full study, 198 (54.2%) were male, and 167 (45.7%) were female
patients. The mean age of these cases was 58.64± 11.4. Of the 365 study
participants who received prophylactic antibiotics prior to surgery, 16
patients developed surgical site infections (legs and sternum). Among
these 16 patients, nine cases belong to the 7-days prophylactic
antibiotic therapy group (2.4%), and seven cases belong to the 2-day
prophylactic antibiotic therapy group (1.9%) (P=0.771).
Conclusion: Comparison of two 2-day and 7-day
prophylactic antibiotic regimens showed no significant difference in the
incidence of post-surgical infection in the two groups.
Keywords: Surgical Wound Infection; Coronary Artery Bypass;
Antibiotic Prophylaxis
Introduction
Postoperative administration of antibiotics is frequently useless, and
even some studies have shown that it is detrimental to the patients.
Principals of prophylaxis antibiotics are based on the type of
antimicrobial used, time of the first dose, and duration of the
prophylactic regimen used 1. Among the several types
of antibiotics, cephalosporins are the preferred choice for many since
they are less allergic to recipients than penicillins2. Accordingly, first-generation cephalosporins,
cefazolin, have been recommended for various surgical procedures due to
their significant benefits, especially with anti -Staphylococcuseffects 3. Surgical site infections (SSIs) occur more
than a month after surgery and affect many tissues at the operation
site. About 3% of the surgical patients develop a surgical site
infection 4. Among these infections, prevention of
cardiac surgical site infections, including mediastinitis and sternal
infection, have become the main sections on improving hospital
performance and quality and cost control plans. The incidence of cardiac
surgical site infections or coronary artery bypass grafting (CABG)
surgery infections ranges from 0.35 to 8.49 cases per 100 operations for
sternal sites 5. A pre-operative antibiotics therapy
is an effective strategy to reduce the incidence of SSIs. Despite the
generalization that pre-operative antibiotic therapy is beneficial for
reducing surgical site infections, there is no consensus on the onset,
type, and duration of the antibiotic therapy 6.
According to some studies, the best duration of treatment for antibiotic
prophylaxis is short-term, for example, 48 hours prior to surgery7. Several reports have indicated that short-term
prophylaxis protection lasts only for 4 days and is ineffective in
reducing infections. Extended prophylaxis of antibiotic therapy was also
found to be associated with a risk of Clostridium difficileinfection after coronary artery graft bypass surgery in some studies.
Therefore, a consensus has emerged in the medical community to
standardize the practice associated with prophylactic antibiotic therapy
duration, reduce the development of antibiotic-resistant Clostridium
difficile infection, and reduce the treatment cost 8.
Due to the incidence of surgical site infections and the lack of
definitive guidelines for the duration of antibiotic prophylaxis, we
aimed to compare two durations of the regular antibiotic treatment
regimens in patients undergoing CABG in Ayatollah Rouhani Hospital,
northern Iran.
Materials and methods
This study was performed as a prospective, randomized, double-blind
placebo-controlled trial. The study population consisted of all patients
who underwent coronary artery bypass graft surgery at Ayatollah Rouhani
Hospital, Babol, northern Iran, during 2016-2017. This 511-bed hospital
serves more than two million residents of Mazandaran province, North of
Iran. Also, over the year, 700 heart surgery operations have been
performed in the treatment center. The inclusion criteria were patients’
willingness to participate in the study with informed consent and the
age range of 18 to 80 years old who underwent coronary artery bypass
graft surgery. Patients with the previous infection and antibiotic usage
recently (in the last one month), renal failure (creatinine level
greater than 2 mg/dL in two repetitive tests), cardiac ejection fraction
(EF) less than 30%, liver failure, severe systemic illness or usage of
drugs that lead to immunodeficiency, coincidences with other cardiac
surgeries (valve surgery), re-surgery in the same area, and history of
antibiotic hypersensitivity to the cefazolin and cephalexin antibiotics
used in this study were excluded. Moreover, the patients who were under
mechanical ventilation for more than 24 hours or stayed in the intensive
care unit (ICU) for more than 3 days, along with off-pump surgery, blood
transfusion of more than 6 units per day, surgery duration greater than
6 hours, or pump time greater than 120 minutes or aortic clamping time
greater than 60 minutes, the need for intra-aortic balloon pump or
inotropic doses higher than the median doses, and emergency surgeries
were excluded.
Based on the prevalence of CABG infection with antibiotic prophylaxis
(6%) 9,10, 370 cases were considered. After obtaining
the necessary permissions and registering on the Iranian Registry of
Clinical Trials (IRCT201707188968N2), obtaining informed consent from
the patients, and applying exclusion criteria, all of the mentioned
patients were included in the study.
All patients were showered the night before surgery, and the surgical
cutting site was shaved. In the operating room, the incisional site was
prepared with iodopovidone solution. Disposable shampoos and sterile
operating room appliances were the same for all cases. In terms of ICU,
the cardiopulmonary pump, anesthesia, and ward matching technique and
equipment were done among the patients.
After entering the operating room, an expert randomly assigned patients
to one of the groups (185 cases per treatment). At the time of induction
of anesthesia and before surgery, cefazolin (2g, IV) was given. The
second dose of cefazolin was given if the duration of the surgery lasted
longer than 5 hours. After surgery, they were divided into 2 groups.
Both groups, cefazolin (1g, IV), was administered every 6 hours for 2
days. Moreover, group I received placebo capsules (containing starch)
every 6 hours for 5 days, and group II received cefalexin 500 mg capsule
every six hours for 5 days. Demographic and clinical characteristics of
the patients, including age, gender, diabetes, body mass index (BMI),
smoking, systemic hypertension, graft number, cardiopulmonary bypass
duration, cardiac ejection fraction, ICU duration, time of intubation,
creatinine, and blood urea nitrogen (BUN) were entered into the data
collection form. Moreover, all patients received training on the
symptoms of wound infection.
Patients were evaluated for evidence of SSIs on days 3, 7, 10, 30, and
90 after operation by the surgeon. As an indication of SSI, patients
were examined for oozing pus around the incisional site, body
temperature above 38 °C, redness, pain, and warmness of the skin.
Results were recorded in the data collection forms. In the case of
secretion, a sample wound was sent for culture. Surgeons have also
warned patients about the complications of surgical site infections (in
the sternum and legs). Criteria for superficial SSIs were considered as
one of the following: pussy oozing of incisional site, positive
microbial culture from a sample collected at the incision site,
inflammatory symptoms. Detection of deep SSIs is also based on pussy
drainage from deep tissue, re-opening of incision spontaneously or by a
surgeon due to fever, or localized pain or tenderness.
In this study, the primary criterion for SSI has wound infection at the
incisional site. After collecting and categorizing information, all
statistical analysis was done using SPSS v.16.0 (IBM Corp., Armonk, NY,
USA). Moreover, it is worth noting that the antibiotic treatment details
of the patients were kept as blindness for the statistician to avoid any
bias. The comparison of quantitative variables was made by student
t-test, whereas Chi-square and Fisher exact tests compared qualitative
variables. The level of significance in all tests was considered to be
< 0.05.
Results
This study enrolled 370 patients undergoing coronary artery bypass graft
surgery to evaluate the prophylactic antibiotic duration practices post
CABG. Among the study participants, five cases were excluded since two
patients died and three patients did not fulfill the course of study
during 1-month follow-up (Figure1). Of the remaining 365 patients, 198
(54.2%) were male, and 167 (45.7%) were female, and also, the mean age
of these cases was 58.64 ± 11.4. One hundred and eighty-two patients in
group I received one antibiotic for 2-days, and 183 patients in group II
received antibiotics for 7-days. Both the groups did not show a
significant difference in sex, mean age, body mass index. In twenty
patients (4.5% of total participants), the surgery lasted more than 5
hours and thus received a second dose of intravenous antibiotics. There
was no significant difference in the number of operations over 5 hours
since13 cases in group I (7%) and seven cases in group II (3.8%)
belong to this category (p = 0.251). All subjects’ mean body mass index
was 25.92 ± 3.41 kg/m2. The surgery period was
variable from 3 hours to 6 hours, and the mean duration of all surgeries
was 4.29 ± 0.56 hours (Table 1). The frequencies of comorbidities in
these two groups were not significantly different (Table 2). Evidence of
SSIs (leg or sternum) was reported in 16 out of 365 patients who have
undergone surgery. Nine cases in group II and 7 cases in group I.
Relative risk, RR=0.7 (95% Confidence Intervals: 0.22-2.26; p=0.771).
The incidence of infection in all subjects in the two groups was 4.3%.
One case of mediastinitis was seen (0.21%) in group II. The location,
depth, and incidence of surgical site infections in the two groups were
also shown in Table 3. Among sixteen patients with evidence of SSIs, 12
patients had positive microbial cultures (75%). Positive cultures were
seen in 7 patients in group I and 5 patients in group II, but the
frequency of infection in the two groups was not significantly different
(p = 0.681). Of these 12 cases, Escherichia coli (E.coli )
was the most common microorganism (7 cases). Staphylococcus
epidermis in 3 patients and Pseudomonas aeruginosa in 2 cases
were also isolated. Antibiotic susceptibility showed in Table 4.
Discussion
The use of antibiotics to prevent surgical site infections is shown to
be unnecessary after surgery. Many studies have shown that antibiotics
are beneficial before surgery, especially for heart surgeries11,12. However, the effectiveness of these antibiotics
concerning the duration of their use prior to surgery is not very clear.
This case has been studied in various sources and numerous clinical
trials. Some trials in heart surgery suggested that increasing the
duration of antibiotic prophylaxis does not significantly decrease
surgical site infections 13.
The duration of antibiotic therapy before surgery, especially in CABG,
is still debatable, and for this reason, we examined this critical
issue. This study showed no significant difference in the incidence of
infection in two groups (antibiotic for 2-days versus 7-days) to prevent
postoperative infections in coronary artery bypass graft surgery. These
findings are consistent with the findings of Paul et al.14, which showed that increasing the duration of
antibiotic prophylaxis in patients undergoing cardiac surgery does not
significantly reduce surgical infections. According to the current
study, the incidence of SSIs in 365 patients undergoing surgery was 16
patients. The findings of SSI incidence were also similar to studies by
Gelijns et al. 15. However, in studies by Farrington
et al. and Bhatia et al., the rate of occurrence of infection was higher
than the current study, with 14.3% 18%rates, respectively16,17.
Of the 16 patients, 9 cases were in group II, and 7 were in group I,
which was not statistically significant. It shows that longer antibiotic
use was not beneficial; this may have had harmful effects for the
patients. The number of positive microbial cultures in group I was more
than group II (7 patients in group I versus 5 cases in group II) with no
significant difference between groups, indicating that antibiotic use
could only negatively affect culture. Moreover, it suggested that
prolonging the antibiotic regimen does not reduce infections, but
changing the normal flora may increase the incidence of infection and
the emergence of resistant organisms.
Surgical site infections in cardiac surgery, including sternal and
mediastinal infections, cause an increase in treatment costs and
increased morbidity and mortality. Bhatia and colleagues17 described sternum and legs as the most common
infection in patients undergoing coronary artery bypass graft surgery,
which is consistent with the results of our study. It showed an overall
high rate of infection in the lower extremities. Long-term treatment
versus short-term is unlikely to cause mediastinitis since only one case
was seen with these symptoms. This result is consistent with the study
by Lador et al., which showed no association between the increase in
antibiotic duration and the reduction of deep infection18. As mentioned, infection was mostly found in the
foot. The team that removes the veins is separate from the heart surgery
team, and the creation of hematoma is considered an important factor in
wound infections. Moreover, the time for the discontinuation of the
heparin drug is different from the heart surgery team and vascular
surgeons, which helps to create an infection, and also because the leg
is considered to be the lower extremities and its blood supply is more
difficult than other upper organs, the infections are more likely to
occur. Therefore, it is suggested that the studies be conducted on the
exact time to discontinue heparin treatment. By reducing hematoma, the
chance of developing foot infections is also reduced.
The predominant organism responsible for cardiac SSIs is gram-positive
staphylococcal species. First-generation cephalosporins are preferred
for prophylactic antibiotic therapy 19. Except in
cases with a proven allergy to beta-lactam antibiotics, using
cephalosporin (a beta-lactam group antibiotic) as a prophylactic drug
for 24 to 48 hours is considered the most logical treatment choice.
Gram-negative organisms may cause infections of the sternum wounds after
coronary artery bypass graft surgery, possibly due to the transposition
of the organism during the removal of the vein. In the s tudy by
Heydarpour et al ., most organisms isolated were gentamicin
resistant 20, whereas the current study showed
organisms with the highest resistance to ciprofloxacin. Seven cases of
12 positive cultures were resistant to ciprofloxacin, and the organism
that showed resistance in both groups was E.coli .
This study has not been carried out in large communities, and it is
advisable to undertake such studies with a large sample size to confirm
that a 2-day antibiotic regimen has a relatively equal effect with
longer ones.
Conclusion
This study revealed no significant difference in the incidence of
infection in two groups (first-generation cephalosporins for 2-days
against 7-days) to prevent postoperative infections in CABG. Such
findings can help reduce the overall antibiotic use, cost, and the
development of antibiotic resistance.